Coma and consciousness: paradigms (re)framed by neuroimaging.

TL;DR: Advances in measurement support a model of consciousness as the emergent property of the collective behavior of widespread frontoparietal network connectivity modulated by specific forebrain circuit mechanisms.

About: This article is published in NeuroImage.The article was published on 2012-06-01 and is currently open access. It has received 330 citations till now. The article focuses on the topics: Consciousness.

Summary

Keywords

• Coma, vegetative state, minimally conscious state, fMRI, PET, consciousness, traumatic brain injury *7.
• Manuscript Click here to view linked References.

Key Points

• Neuroimaging shows cognition in some patients without motor responsiveness.
• This improves clinical and pain management of chronic disorders of consciousness.
• It permits selection for thalamic deep brain stimulation and plasticity enhancement Awareness depends on frontoparietal & mesocircuit functional connectivity Multi-center studies are offering evidence-based diagnostic and prognostic tests.

A brief history of coma

• The invention of the artificial respirator in the 1950s made it possible for many patients to ―survive‖ their brain damage and led to the redefinition of death based on brain function criteria (i.e., brain death or irreversible coma with absent brainstem reflexes, and to the identification of locked-in syndrome or pseudo-coma (for review see e.g., Laureys, 2005b).
• Unfortunately persistent and permanent VS share the abbreviation ―PVS‖ often leading to unwarranted confusion.
• Emergence from MCS was defined by functional communication or functional use of objects.
• While such a conflation has always implied a failure to adhere to the strict definitions of VS, as MCS explicitly subcategorizes patients within the overly broad category of severe disability and not a subset of patients that would have fulfilled the definitional criteria for VS.
• As the authors will see, recent studies have demonstrated it is important to disentangle both clinical entities as functional neuroimaging have shown differences in residual cerebral processing and hence, conscious perception (Boly et al., 2008a; Coleman et al., 2009; Rodriguez Moreno et al., 2010; Vanhaudenhuyse et al., 2010), as well as important differences in outcome (e.g., Luaute et al.).

The challenge of measuring consciousness

• For neurologists, consciousness can be reduced to arousal (i.e., wakefulness or vigilance) and awareness (i.e., comprising all subjective perceptions, feelings and thoughts) (Posner et al., 2007).
• Awareness in turn can be divided into ―external awareness‖ (i.e., sensory or perceptual awareness of the environment) and ―internal awareness‖ (i.e., stimulusindependent thoughts, mental imagery, inner speech, daydreaming or mind wandering) (Vanhaudenhuyse et al., 2011).
• Clinically, arousal is typically measured by examining eyeopening and reproducible command-following to establish proof of awareness.
• The bedside examination of consciousness in severely brain damaged patients, however, is extremely challenging because movements can be very small, inconsistent and easily exhausted, potentially leading to diagnostic errors.
• This issue is further complicated when patients have underlying deficits in the domain of verbal or non-verbal communication functions, such as aphasia, agnosia or apraxia (Bruno et al., 2010a; Majerus et al., 2009; 2005).

Measuring the brain at “rest”

• Voxel-based statistical analytical tools next permitted to recognize not only global or a priori defined region-of-interest changes in brain function but more detailed data-driven regional differences and more importantly assessed changes in effective connectivity when VS was compared with healthy conscious waking.
• Structural MRI studies such as diffusion tensor imaging also permit to quantify lesions to the brain‘s white matter tracts in severe brain injury, often invisible to conventional radiological approaches (Newcombe et al., 2010) and may help differentiating VS from MCS (2010a).
• The study of VS patients who subsequently recovered offered an additional causal link between consciousness and the functional integrity of this long-range frontoparietal network – pointing to the role of non-specific (central intralaminar) thalamic projections in the support of these large-scale distributed cortico-cortical connections (Laureys et al., 2000b).

INSERT TABLE 1

• From “Activation” studies to passive stimulations Menon et al. (1998b) first claimed to have demonstrated residual ‗cognition‘ in a VS patient using functional neuroimaging techniques.
• These findings should strongly influence physicians to systematically use analgesic agents in MCS patients, even if (by definition) they cannot communicate their sensations (Schnakers et al., 2010).
• Bardin et al. (2011b) demonstrated two examples where fMRI based command following did not lead to communication using this signal.
• This methodology was also adapted by asking patients to count the number of deviant trials in an auditory oddball series (Bekinschtein et al., 2009a).

INSERT TABLE 3

• Table 3 offers an overview of the fMRI, EEG, evoked potential and EMG studies aiming to show signs of consciousness and communication not accessible by bedside behavioral examination.
• The clinical management of these disorders of consciousness remains very challenging, but technological advances in neuroimaging are now offering new ways to improve their diagnosis.
• Taken together, with the studies of passive stimuli in MCS patients, these findings suggested that relatively intact cerebral integrative processes remained, but like the unreliable behavioral responsiveness seen in these patients, neuronal responses were similarly unstable.
• These brain regions are known to have a very high resting metabolic rate that dominates the pattern of resting brain activity and may represent a ‗default‘ state as proposed by Raichle (2007).
• A proof-of-concept study demonstrated that despite long-standing MCS level function, a patient 6 years after injury recovered multiple cognitively-mediated behaviors after placement of bilateral central thalamic deep brain stimulation electrodes (Schiff et al., 2007).

Modeling consciousness

• An organizing mesocircuit model provides an economical explanation of the vulnerability of the anterior forebrain in the setting of widespread deafferentation and neuronal cell loss associated with a variety of severe brain injuries that produce unstable levels of behavioral responsiveness associated with MCS and patients just past the border of MCS in confusional state .
• The thalamocortical projections from the central thalamus strongly innervate both the frontal cortex and the striatum (see refs for further details Schiff, 2010).
• Schnakers et al. (2008a) showed specific changes in frontoparietal metabolism induced by amantadine .

A common model for changes in precuneus/posterior medial parietal complex and

• Anterior forebrain mesocircuit during recovery of consciousness.
• This pattern of evoked cerebral activity is consistent with projections from the central thalamus to medial parietal cortical regions.
• A longitudinal assessment of this patient identified regions that showed significant change in measured fractional anisotropy over a 18 month time period beginning over 20 years following injury.
• It is clear from this overview that their understanding of consciousness and disorders of consciousness after coma is currently witnessing a significant paradigm shift (Laureys and Boly, 2008; Owen et al., 2009).
• Moreover, for the group of patients with capacity to communicate these scientific discoveries bear on their fundamental rights for accurate diagnostic assessments and the basics of clinical care (Fins, 2009b; Fins et al., 2008b).

Figures

• The monolithic way of looking at severe brain damage (in grey) is being replaced by a more graded nosology (in white) based on quantitative behavioral assessments and functional neuroimaging methods.
• Low level activation 3 VS High level activation 5 MCS Low/high level activation (Fernandez-Espejo et al., 2008) 7 2 VS TBI 1-11m auditory (forward/backward speech) 2011 fMRI 5/43 included VS 4TBI 1TBI-anoxic 10d Motor task Activation of contralateral dorsal premotor cortex in 2VS Bardin et al.
• Yes (motor mental imagery) -or-no (spatial mental imagery) autobiographical questions.

Figures

Figure 2. Loss of functional connectivity and modularity in the vegetative state.

Figure 1 Changing view on chronic disorders of consciousness.

Figure 6. Linking models of spontaneous and induced recovery of consciousness: the possible interactions of the anterior forebrain mesocircuit and posterior medial complex.

Figure 5. Proof of concept that central thalamic deep brain stimulation can facilitate recovery of behavioral responsiveness in the chronic minimally conscious state.

Table 1. Functional neuroimaging data of the past 25 years measuring brain function in ―resting state‖ conditions using (1) fluorodeoxyglucose positron emission tomography (FDG-PET) and (2) functional magnetic resonance imaging (fMRI) in chronic disorders of consciousness.

Table 3. Functional neuroimaging studies using ―active” tasks assessing (1) consciousness or (2) communication using fMRI, evoked potentials or electromyography in chronic disorders of consciousness.

Figure 4. Assessment of command following and communication using functional neuroimaging.

Table 2. Functional neuroimaging studies measuring brain activation to ―passive” sensory stimulation using (1) H2 15 O PET (2) MEG and (3) fMRI in chronic disorders of consciousness.

Figure 3. Role of posterior medial complex in process of recovery of consciousness.

Frequently asked questions

Q1. What did the authors claim to have demonstrated in a VSpatient?

From “Activation” studies to passive stimulationsMenon et al. (1998b) first claimed to have demonstrated residual ‗cognition‘ in a VSpatient using functional neuroimaging techniques. 

Q2. What is the role of the central lateral nucleus in the human thalamus?

In the human thalamus, the central lateral nucleus and surrounding paralaminar regions receive the heaviest innervations of both brainstem and basal forebrain cholinergic systems and project widely to supergranular cortical regions (Heckers et al., 1992; Van der Werf et al., 2002). 

Q3. What are the main mechanisms that require other mechanisms to support the conscious state?

These observations require other mechanisms that in addition to axonal regrowth likely include changes in synaptic efficacy, pools of available receptors and other fundamental alterations in the cellular profile of individual neurons over time as brain state changes. 

Q4. What is the counterintuitive set of observations of behavioral improvements associated with pharmacological?

Perhaps the most counterintuitive set of observations of behavioral improvements associated with pharmacological interventions in MCS patients accounted for by the model is the quite paradoxical phenomenon of marked behavioral facilitation occasionally observed with administration of the sedative agent zolpidem (a non-benzodiazepine hypnotic that potentiatesGABA-A alpha 1 receptors, (Brefel-Courbon et al., 2007; Clauss and Nel, 2006; Schiff and Posner, 2007). 

Q5. What is the effect of disfacilitation on background firing rates?

Experimental studies demonstrate that powerful consequences on background firing rates occur even with disfacilitation producing only modest reductions in cerebral blood flow (Gold and Lauritzen, 2002).